Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis.
Active immunization against the vascular endothelial growth factor receptor flk1 inhibits tumor angiogenesis and metastasis.
复制标题
针对血管内皮生长因子受体FLK1的主动免疫抑制肿瘤血管生成和转移。
DOI：
10.1084/jem.20020072
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发表时间：
2002-06-17
影响因子：
15.3
通讯作者：
Hicklin, Daniel J
中科院分区：
文献类型：
--
作者：
Li, Yiwen;Wang, Mei-Nai;Li, Hongli;King, Karen D;Bassi, Rajiv;Sun, Haijun;Santiago, Angel;Hooper, Andrea T;Bohlen, Peter;Hicklin, Daniel J
血管内皮生长因子（VEGF）受体胎肝激酶1（flk 1; VEGFR-2，KDR）是一种内皮细胞特异性受体酪氨酸激酶，介导生理和病理性血管生成。我们假设以flk 1为靶点的主动免疫疗法可能抑制肿瘤血管生成和转移。为了验证这一假设，我们首先评估是否可以通过用可溶性flk 1蛋白（DC-flk 1）脉冲的树突状细胞免疫小鼠来引起对flk 1的免疫应答。该免疫产生flk 1特异性中和抗体和CD 8+细胞毒性T细胞应答，打破了对自身flk 1抗原的耐受性。肿瘤诱导的血管生成抑制免疫小鼠中测量的藻酸盐珠测定。在用B16黑色素瘤或刘易斯肺癌细胞攻击的DC-flk 1免疫小鼠中，肺转移的发展被强烈抑制。DC-flk 1免疫还显著延长了用刘易斯肺肿瘤攻击的小鼠的存活。因此，靶向内皮上的血管生成相关抗原的主动免疫策略可以抑制血管生成，并且可能是治疗血管生成相关疾病的有用方法。
The vascular endothelial growth factor (VEGF) receptor fetal liver kinase 1 (flk1; VEGFR-2, KDR) is an endothelial cell–specific receptor tyrosine kinase that mediates physiological and pathological angiogenesis. We hypothesized that an active immunotherapy approach targeting flk1 may inhibit tumor angiogenesis and metastasis. To test this hypothesis, we first evaluated whether immune responses to flk1 could be elicited in mice by immunization with dendritic cells pulsed with a soluble flk1 protein (DC-flk1). This immunization generated flk1-specific neutralizing antibody and CD8+ cytotoxic T cell responses, breaking tolerance to self-flk1 antigen. Tumor-induced angiogenesis was suppressed in immunized mice as measured in an alginate bead assay. Development of pulmonary metastases was strongly inhibited in DC-flk1–immunized mice challenged with B16 melanoma or Lewis lung carcinoma cells. DC-flk1 immunization also significantly prolonged the survival of mice challenged with Lewis lung tumors. Thus, an active immunization strategy that targets an angiogenesis-related antigen on endothelium can inhibit angiogenesis and may be a useful approach for treating angiogenesis-related diseases.